Dear Certara Team
I am conducting a PK analysis on a rich/dense dataset from an study with an continuous i.v. infusion over 90 minutes (no bolus).
Previous NCA analysis seem to indicate distributional kinetics. The kinetics seem to be similar to for instance propofol; elimination is rapid and distribution into deeper compartments is slow. The concentration rises rapidly within the first 20 - 30 minutes, then slowly until reaching steady state at about 70 -80 minutes. After stopping the infusion, the concentration decreases rapidly initially (propably reflecting elimination from plasma/interstitium) and then more slowly (reflecting redistribution from tissue).
I am now setting up an individual PK model with your least squares regression models. I use a two compartment model (micro-constants, model 9). However, even though the fitted models look more or less ok on diagnostic plots (obs. vs. pred. and residual plots, weighted correlation 0.93), the fitted parameters don't really make sense. k12 is much smaller than k21 and V1 is much larger than V2, even though I would expect the exact opposite (small V1 reflecting plasma/interstitium, large V2 reflecting deeper tissues). Also, the variances of many parameter estimates are extremly inflated, indicating that something is clearly wrong.
Any suggestions what is wrong? Is it the wrong model for these rather unusual kinetics, where elimination is faster than distribution? Do I need to use user supplied bounds?
Many thanks in advance for your help